Is ENG p.Val592Met (c.1774G>A) pathogenic?

ENG p.Val592Met (c.1774G>A) is classified Uncertain significance in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.3956); Very rare (popmax 0.00442%, sas); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Val592Met (c.1774G>A)?

ENG p.Val592Met (c.1774G>A) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Val592Met (c.1774G>A) in the general population?

ENG p.Val592Met (c.1774G>A) is very rare (popmax 0.00442%, sas) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ENG p.Val592Met (c.1774G>A)?

AlphaMissense predicts ambiguous (score 0.3956) — an in-silico prediction, not a clinical call.

ENG p.Val592Met

c.1774G>A · rs756003321 · VCV1001852

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00442%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.3956	ambiguous
REVEL	0.268	benign-leaning
SaProt	LLR -11.58	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00442% South Asian · 4/90,476 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000896%

Overall 0.000807% 13/1,610,758 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00442%	22,619
Finnishnot grpmax-eligible	0.00317%	31,554
Admixed American	0.00168%	59,650
European (non-Finnish)	0.000509%	196,530

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ENG
Protein: p.Val592Met
Coding: c.1774G>A
MANE Select: NM_001114753
dbSNP: rs756003321
Type: single nucleotide variant
Location: chr9:127816021 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB

Full ENG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary hemorrhagic telangiectasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ENG p.Arg529His Pathogenic ★★★ ⚠ same condition
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same condition
ENG p.Cys382Tyr Pathogenic ★★★ same condition
ENG p.Cys549Gly Likely pathogenic ★★★ same condition
ENG p.Gly331Ser Pathogenic ★★★ ⚠ same condition
ENG p.Gly603Arg Likely pathogenic ★★★ same condition
ENG p.Leu221Pro Likely pathogenic ★★★ same condition
ENG p.Leu506His Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/eng-p-val592met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown